Speakers

UPS impairment has been implicated as a contributing factor in multiple human neurodegenerative diseases, such as Amyotrophic Lateral Sclerosis (ALS), Alzheimer’s disease (AD), and Parkinson’s disease (PD). Through an inhibitor screening of kinases that were upregulated in SOD1 ALS model, we identified the kinase as a novel modifier of neuronal toxicity caused by UPS impairment. Furthermore, we showed that downregulation of this kinase mitigated the neuronal cell death induced by UPS impairment in mammalian cultured neuronal cells and flies. We found that overexpression of Tar DNA-binding protein 43 (TDP-43) as well as co-expression of TDP-43 with ALS-linked Ataxin-2 (ATXN2) led to UPS impairment. Suppressor of UPS impairment toxicity also mitigates the climbing and survival defect of TDP-43 proteinopathy fly and mammalian cell line model. Moreover, inhibition of the kinase significantly increased the protein level of p62, and down-regulation of p62 completely blocked neuroprotection of this kinase in UPS impairment condition. Taken together, these findings suggest that downregulation of the kinase that mitigates neuronal toxicity caused by UPS impairment in a p62 dependent manner may represent a novel therapeutic approach for neurodegenerative diseases such as AD, PD and ALS.